This invention relates to a process for preparing a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative exhibiting antitumor and antiviral activities.
1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluorom ethyluracil derivatives (trifluorothymidine derivatives) have attracted attention for many years in terms of their association with nucleic acid bases, uridine and thymidine. In particular, since they exhibit antitumor and antiviral activities, they have been intensely investigated for production as a medical drug or an important intermediate therefor. It is well known in this art that a preparation process considerably depends on the type of a nucleic acid base and that a superior preparation process must be studied for each base.
For example, as described in Nucleic Acid Research 12 6827 (1984) and Nucleosides and Nucleotides 8 549 (1989), a nucleic acid base such as uracil, fluorouracil, thymine and trifluorothymine drastically changes its properties, depending on a substituent on the 5-position. Thus, in its preparation by glycosylation, a process suitable to each reaction must be investigated. In particular, in 5-trifluorouridine, to which this invention is directed, the trifluoromethyl group significantly influences to give the chemical properties of the compound greatly different from unsubstituted uridine or thymidine and reduces a selectivity between xcex1- and xcex2-forms in glycosylation. It has been, therefore, difficult to establish an industrial process for preparing the xcex2-form which is practically needed.
Conventional processes for preparing a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative are;
(1) exchanging a nucleic acid base from thymidine and 5-trifluoromethyluracil by, for example, nucleoside-2xe2x80x2-deoxyribose transferase [M. G. Stout, et al., Methods Carbohydr. Res., 7, 19 (1976)];
(2) reacting a halogen atom on the 5-position in a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-halouracyl derivative with trifluoromethyl copper [Y. Kobayashi, et al., J. C. S. Perkin TransI, 2755 (1980)];
(3) electrolysis of an uridine derivative and trifluoroacetic acid [L. Hein, et al., DE 119423 (1976)];
(4) reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine with a methyl 2-deoxy-D-erythro-pentofuranoside derivative in the presence of an acid catalyst [National Publication of the International Patent Application No. 500239-1987];
(5) increasing a molar ratio of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine in its reaction with 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-xcex1-D-erythro-pentofuran osyl chloride or conducting the reaction in the presence of a zinc chloride catalyst [Japanese Patent Laid-Open No. 2-289595; Heterocycles, 31, 569 (1990)].
However, the process described in (1) has a drawback that it is difficult to isolate and purify the desired product from a reaction system. The process, therefore, cannot be suitably applied to large scale synthesis. The process described in (2) has a drawback that a reaction intermediate is quite sensitive to, for example, air. The process described in (3) has a drawback that both yield and current efficiency are low and electric facilities resistant to trifluoroacetic acid are required. The process described in (4) has a drawback that a product is obtained as a mixture of xcex1- and xcex2-forms which cannot be readily separated so that an isolation yield for the desired xcex2-form is extremely low.
For the process described in (5), referring to the reaction analysis values described in the literature, one mole of 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-xcex1-D-erythro-pentofuran osyl chloride is treated dropwise with a solution of two moles of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine in chloroform (on the basis of calculation from the values in the literature, an 11.1-fold amount of chloroform to the total amount of 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-xcex1-D-erythro-pentofuran osyl chloride and 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine) to give a selectivity of xcex2/xcex1 form=56/44 while being treated with 8 moles to give a selectivity of xcex2/xcex1 form=74/26.
Zinc chloride may be added instead of increasing a molar ratio of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine to 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-xcex1-D-erythro-pentofuran osyl chloride to improve a selectivity of xcex2/xcex1 form=about 75/25. The process has an economically and industrially significant drawback that it uses a largely excessive amount of quite expensive 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine and either procedure cannot give a practical xcex2-selectivity.
Thus, no conventional preparation processes can be suitably applied to stable and low-cost large scale production of a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative important as a medical drug or an intermediate therefor and an improved and useful process has been needed.
An objective of this invention is to solve the above problems in conventional preparation processes and provide a process for preparing a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative with an improved-selectivity by lower-cost and convenient steps.
We have investigated preparation of a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative by reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine with a 2-deoxy-xcex1-D-erythro-pentofuranosyl chloride derivative and have found that in a solvent free system the reaction may proceed with a very high selectivity of xcex2/xcex1 form=96/4. We have also found that a solvent may be added up to a 4-fold mass to the total mass of the reactants for avoiding a tendency to difficulty in stirring due to increased viscosity of the reactants as the reaction proceeds in the solvent free reaction to ensure smooth stirring and good operability and to provide the xcex2-form of the desired product, the 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative, with an improved selectivity. This invention has been achieved on the basis of these findings.
One aspect of a process for preparing a trifluorothymidine derivative according to this invention comprises the step of reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine represented by formula (1): 
as a first material, with a 2-deoxy-xcex1-D-erythro-pentofuranosyl chloride derivative represented by formula (2): 
wherein X represents a halogen atom; X1 and X2 independently represent a hydrogen atom, methyl group or halogen atom, as a second material in a solvent free system to give a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative represented by formula (3): 
Another aspect of a process for preparing a trifluorothymidine derivative according to this invention comprises the step of reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine represented by formula (1): 
as a first material, with a 2-deoxy-xcex1-D-erythro-pentofuranosyl chloride derivative represented by formula (2): 
wherein X represents a halogen atom; X1 and X2 independently represent a hydrogen atom, methyl group or halogen atom, as a second material in the presence of a solvent to give a 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative represented by formula (3): 
in which the solvent is used in an amount not exceeding a 4-fold mass to the total mass of the first and the second materials.
In the process of the first aspect of this invention, the reaction may be initiated in a solvent free system and then a solvent may be added to the reaction system to conduct the reaction in the presence of the solvent.
According to this invention, since the reaction stoichiometrically proceeds, materials unstable in the air may be used in a needed amount, resulting in effective use of the materials and elimination of a step for recovering remaining materials.
This invention will be described in detail.
Two starting materials are used in a preparation process according to this invention. First, 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine as a first material may be readily prepared by a known procedure from a known compound, 5-trifluoromethyluracil (See, for example, T. A. Khawaja, et al., J. Med. Chem., 12, 543 (1969)).
A 2-deoxy-xcex1-D-erythro-pentofuranosyl chloride derivative as a second material may be also prepared in several steps by a known process from a readily available starting material, 2-deoxyribose. For example, as a representative example, 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-xcex1-D-erythro-pentofuran osyl chloride may be prepared using 2-deoxyribose as a starting material according to J. J. Fox, et al., J. Am. Chem. Soc., 83, 4066 (1961).
A molar ratio of the first/the second materials used in this invention is preferably 0.5 to 2 both inclusive, and economically the upper limit of the range is more preferably 1.
The reaction between the first and the second materials in this invention is conducted in the absence or presence of a solvent in a given amount or less. There are no restrictions to a solvent used in this invention as long as it is aprotic. Preferable examples of such an aprotic solvent include aromatic solvents such as 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, anisole, toluene and nitrobenzene; ethers such as diisopropyl ether, diethyl ether, tetrahydrofuran and dioxane; esters such as ethyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogenated aliphatic solvents such as chloroform and methylene chloride. A solvent may be constituted by at least one of these. Halogenated aromatic solvents such as 1,2,4-trichlorobenzene, o-dichlorobenzene and chlorobenzene are herein categorized in aromatic solvents. More preferable solvents include 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, anisole, toluene and methyl isobutyl ketone.
The amount of a solvent used is up to 4-fold to the total mass of the first and the second materials, more preferably up to the total mass of the first and the second materials. If the amount is more than 4-fold, a xcex2-selectivity may be reduced so that the objective of this invention cannot be achieved.
A solvent may be added to the reaction system after premixing it with at least one of the first and the second materials. A solvent may be added immediately after blending the first and the second materials or while the reaction proceeds after blending the first and the second materials.
An additive such as metal salts, ammonium salts and acids may be added to the reaction system. A metal salt maybe copper fluoride, zinc chloride or tin chloride. An ammonium salt may be tetrabutylammonium fluoride. An acid may be nitrophenol or trifluoromethylsilyl trifluoromethanesulfonate.
A reaction temperature may be xe2x88x9210xc2x0 C. to a boiling point of a solvent used, preferably an ambient temperature to 70xc2x0 C. both inclusive. At a temperature lower than an ambient temperature, the reaction may be slow, while at a temperature higher than 70xc2x0 C. starting materials and/or a product may be decomposed a side reaction may occur. The reaction is generally completed in 0.5 to 48 hours.
It is surprising that a xcex2 selectivity and a yield can be improved in the absence or presence of a small amount of solvent in spite of an equimolar reaction, as apparent from Example 2 described later. The process according to this invention is very advantageous as an industrial preparation process for 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivatives in the light of improvement not only in effective material utilization but also in a reaction volume ratio. Furthermore, this is the first case where the derivative is prepared in the solvent free system. In addition, this is an extremely rare case where there are substantially no restrictions to the type of a solvent as long as its amount is small. These constitute characteristics of this invention.
A 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative may be readily converted into 1-(2xe2x80x2-deoxy-xcex2-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil (trifluorothymidine) important as a medical drug or an intermediate therefor by a known method in a literature such as alkaline hydrolysis.